Apolipoprotein ε4 exacerbates white matter impairment in a mouse model of Aβ amyloidosis by decreasing actively myelinating oligodendrocytes

Previous studies have not combined MRI and histological investigation within the same subjects.

“Notably, previous studies have not combined MRI and histological investigation within the same subjects. 12 , 22 , 26 , 27”

• cites [12] Sun J, Zhu Z, Chen K, et al. APOE ε4 allele accelerates age‐related multi‐cognitive decline and white matter damage in non‐demented elderly. Aging (Albany NY). 2020; 12: 12019‐ 12031. 32572010 PMC7343443 sourceCould not verify

  The Materials and Methods sections on MRI data acquisition and participants describe MRI scans and blood samples for genotyping, but do not discuss histological investigation. Searches for histology combined with MRI in the same subjects found no passage assessing whether previous studies had done so. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites [22] Mirza SS, Saeed U, Knight J, et al. APOE ε4, white matter hyperintensities, and cognition in Alzheimer and Lewy body dementia. Neurology. 2019; 93: e1807‐ e1819. 31575706 PMC6946485 sourceDisputed

  The Methods describe MRI measurements in the Sunnybrook Dementia Study (SDS) sample and postmortem neuropathologic examination of 36 SDS cases. The Discussion also identifies an autopsy-confirmed subset. This cited study therefore combined MRI and histological investigation in some of the same subjects, contrary to the claim that previous studies had not done so. (LLM, conf=0.86)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [26] Mok KK, Yeung SH, Cheng GW, et al. Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte‐derived lipid transport. J Neurochem. 2023; 165: 55‐ 75. 36549843 sourceCould not verify

  The Brightfield Immunohistochemistry and Immunohistochemistry-Immunofluorescence methods sections describe histological imaging of mouse brain tissue. Searches for MRI combined with histology in the same subjects found no passage discussing whether previous studies had done so; the claim cannot be verified from our copy. (LLM, conf=0.73)

  Experimental — accuracy not yet measured

Multiple MRI studies have reported that the APOE4 isoform is associated with white matter degeneration in patients with dementia.

“Multiple MRI studies have reported that APOE4 isoform is associated with white matter degeneration in patients with dementia. 10 , 11 , 22 , 23”

• cites [10] Kumar D, Yatawara C, Wang B, et al. APOE4 and confluent white matter hyperintensities have a synergistic effect on episodic memory impairment in prodromal dementia. J Alzheimers Dis. 2022; 87: 1103‐ 1114. 35431245 sourceNot checked — no full text of the source
• cites [11] Vipin A, Kumar D, Soo SA, et al. APOE4 carrier status determines association between white matter disease and grey matter atrophy in early‐stage dementia. Alzheimers Res Ther. 2023; 15: 103. 37270543 PMC10239168 sourcePartly supported

  The Introduction reports prior associations between APOE4 and white matter hyperintensity burden, an MRI marker of white matter disease, but says findings on APOE4’s influence on that burden are mixed. It does not establish that multiple MRI studies found white matter degeneration specifically in patients with dementia; the Discussion also reports no difference in hyperintensity load between carriers and non-carriers in this study. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [22] Mirza SS, Saeed U, Knight J, et al. APOE ε4, white matter hyperintensities, and cognition in Alzheimer and Lewy body dementia. Neurology. 2019; 93: e1807‐ e1819. 31575706 PMC6946485 sourcePartly supported

  The Discussion reports faster MRI-visible white matter hyperintensity progression in APOE ε4–positive patients with Alzheimer disease, supporting an association in that group. But this paper’s own MRI analyses primarily examine how APOE ε4 modifies the relationship between white matter hyperintensities and cognition in Alzheimer and Lewy body dementia; the Results also report lower hyperintensity volume in homozygous carriers than in other groups. It therefore does not establish the claimed general association between APOE4 and white matter degeneration across patients with dementia. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Even cognitively normal elderly APOE4 carriers exhibit an accelerated decline in white matter integrity.

“Even cognitively normal elderly APOE4 carriers also exhibit an accelerated decline in white matter integrity. 12”

• cites [12] Sun J, Zhu Z, Chen K, et al. APOE ε4 allele accelerates age‐related multi‐cognitive decline and white matter damage in non‐demented elderly. Aging (Albany NY). 2020; 12: 12019‐ 12031. 32572010 PMC7343443 sourcePartly supported

  The Abstract and Discussion report an accelerated age-related reduction in white matter integrity among APOE ε4 carriers compared with noncarriers. However, the Methods define the participants as non-demented, not necessarily cognitively normal, and the Results include participants with mild cognitive impairment. The claim therefore overstates the population studied. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Myelin maintenance in white matter is actively regulated by the continuous proliferation and maturation of oligodendrocytes derived from progenitor cells throughout adulthood.

“Myelin maintenance in white matter is actively regulated by the continuous proliferation and maturation of oligodendrocytes derived from progenitor cells throughout adulthood. 24 , 25”

• cites [24] Young KM, Psachoulia K, Tripathi RB, et al. Oligodendrocyte dynamics in the healthy adult CNS: evidence for myelin remodeling. Neuron. 2013; 77: 873‐ 885. 23473318 PMC3842597 sourcePartly supported

  The Introduction (page not provided) reports that oligodendrocyte precursors continue dividing into adulthood and that some newly formed oligodendrocytes form myelin. The Discussion (page not provided) presents maintenance of existing myelin as a possibility, not an established function of this process throughout white matter; it also considers myelination of previously unmyelinated axons. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [25] Fard MK, van der Meer F, Sánchez P, et al. BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions. Sci Transl Med. 2017; 9: eaam7816. 29212715 PMC7116798 sourcePartly supported

  The Introduction says adult mouse progenitor cells continuously generate oligodendrocytes and that myelination continues into adulthood. But the Results find that early myelinating cells in human white matter become scarce after childhood, while another Results section finds no extensive turnover of myelinating oligodendrocytes in adult mice. The paper therefore does not establish continuous progenitor-derived oligodendrocyte maturation as the mechanism of white-matter myelin maintenance throughout adulthood. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

NODDI provides enhanced sensitivity and specific metrics for detecting Alzheimer's disease-associated microstructural changes.

“In contrast, NODDI provides enhanced sensitivity and specific metrics for detecting AD‐associated microstructural changes. 31 , 32 , 33”

• cites [31] Raghavan S, Reid RI, Przybelski SA, et al. Diffusion models reveal white matter microstructural changes with ageing, pathology and cognition. Brain Commun. 2021; 3: fcab106. 34136811 PMC8202149 sourcePartly supported

  The Discussion (page not provided) reports that NODDI metrics detected Alzheimer’s disease–related white-matter changes and offered more detailed information about neurite health. It does not establish enhanced detection sensitivity over DTI: the Introduction frames that as a hypothesis, and the Discussion says both methods detected subtle Alzheimer’s disease–related changes. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [32] Yu X, Przybelski SA, Reid RI, et al. NODDI in gray matter is a sensitive marker of aging and early AD changes. Alzheimers Dement. 2024; 16: e12627. PMC11284641 39077685 sourceSupported
• cites [33] Colon‐Perez LM, Ibanez KR, Suarez M, et al. Neurite orientation dispersion and density imaging reveals white matter and hippocampal microstructure changes produced by Interleukin‐6 in the TgCRND8 mouse model of amyloidosis. Neuroimage. 2019; 202: 116138. 31472250 PMC6894485 sourcePartly supported

  The Introduction (page not available in our copy) says NODDI provides metrics of axonal and dendritic dispersion and density and reports changes in young-onset Alzheimer’s disease. The Discussion reports changes in those metrics in an amyloidosis mouse model. These passages support the specific-metrics and detection portions of the claim, but do not establish enhanced sensitivity relative to another method. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Previous studies using humanized APOE3 and APOE4 mouse models without amyloid pathology revealed inconsistent findings regarding myelination.

“Previous studies using humanized APOE3 and APOE4 mouse models without amyloid pathology revealed inconsistent findings regarding myelination. One study found no significant difference in myelination, while others observed reduced myelination from electron microscopy images. 27 , 28”

• cites [27] Cheng GW, Mok KK, Yeung SH, Kofler J, Herrup K, Tse KH. Apolipoprotein E ε4 mediates myelin breakdown by targeting oligodendrocytes in sporadic Alzheimer disease. J Neuropathol Exp Neurol. 2022; 81: 717‐ 730. 35779013 PMC9393713 sourcePartly supported

  In “Human APOE Depletes OLs, but Not Myelin Fibers in the Aging Mouse Brain” (page unavailable), the paper reports no difference in MBP-myelinated area between its humanized APOE3 and APOE4 mice. The Discussion (page unavailable) says these mice produce no amyloid plaques unless crossed with another strain. Our copy does not report the claimed reduced myelination in other mouse studies based on electron microscopy, so it does not establish the claimed inconsistency among previous studies. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [28] Blanchard JW, Akay LA, Davila‐Velderrain J, et al. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature. 2022; 611: 769‐ 779. 36385529 PMC9870060 sourcePartly supported

  The Introduction reports that electron microscopy found fewer myelinated axons and thinner myelin sheaths in humanized APOE4/4 mice than in APOE3/3 mice. The Methods identify these as mice with human APOE replacing the mouse gene. Our copy does not report a mouse study finding no significant myelination difference, so it does not establish the claimed inconsistency across studies. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

A post mortem AD study in humans revealed a decrease in NDI in the white matter of APOE4 carriers, suggesting a loss of axons.

“A post mortem AD study in humans revealed a decrease in NDI in the white matter of APOE4 carriers, suggesting a loss of axons. 56”

• cites [56] Slattery CF, Zhang J, Paterson RW, et al. ApoE influences regional white‐matter axonal density loss in Alzheimer's disease. Neurobiol Aging. 2017; 57: 8‐ 17. 28578156 PMC5538347 sourcePartly supported

  The Results report reduced white-matter NDI in APOE ε4-positive patients with young-onset Alzheimer’s disease relative to controls, and the Discussion interprets reduced NDI as modeling axonal loss. But this was a clinical MRI study, not a post-mortem study; the Discussion says post-mortem verification is needed. (LLM, conf=0.91)

  Experimental — accuracy not yet measured

Previous human and animal studies have established the baseline consequences of APOE3 and APOE4 in the absence of amyloid pathology.

“Previous human and animal studies have already established the baseline consequences of APOE3 and APOE4 in the absence of amyloid pathology. 60 , 61 , 62 , 63”

• cites [60] Reiman EM, Arboleda‐Velasquez JF, Quiroz YT, et al. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000‐person neuropathological study. Nat Commun. 2020; 11: 667. 32015339 PMC6997393 sourcePartly supported

  The Results (Neuritic plaque and neurofibrillary tangle severity; page unavailable) compare human APOE3 and APOE4 genotypes and report differences in tau-tangle severity after adjusting for amyloid-plaque severity. Adjustment for plaque severity is not the same as studying consequences in the absence of amyloid pathology. This paper does not itself report an animal study establishing that baseline condition. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [61] Serrano‐Pozo A, Das S, Hyman BT. APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol. 2021; 20: 68‐ 80. 33340485 PMC8096522 sourceSupported
• cites [62] Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013; 9: 106‐ 118. 23296339 PMC3726719 sourceSupported

Among all regions analyzed, the corpus callosum demonstrated the most pronounced alterations across all MRI metrics.

“Among all regions analyzed, the corpus callosum demonstrated the most pronounced alterations across all MRI metrics (Figure 1, topmost row), highlighting its vulnerability to APOE4 genotype‐associated structural changes.”

Network-based statistics revealed disrupted structural connectivity in 5xFAD;APOE4 mice at a statistical threshold of t = 3.0 with the contrast 5xFAD;APOE3 > 5xFAD;APOE4.

“The network‐based statistics analysis revealed disrupted structural connectivity in 5xFAD;APOE4 mice at a statistical threshold of t = 3.0, with the contrast 5xFAD;APOE3 > 5xFAD;APOE4 (Figure 4A–C).”

The left entorhinal cortex had the highest number of connectivity disruptions in the disrupted structural network.

“The left entorhinal cortex had the highest number of connectivity disruptions (Figure 4A, B).”

5xFAD;APOE4 mice had significantly higher isotropic volume fraction in the corpus callosum, hippocampal commissure, and anterior commissure than 5xFAD;APOE3 mice.

“We found a significantly greater ISO value in corpus callosum [t 20 = 3.26, p = 0.003] (Figure 3H), hippocampal commissure [t 20 = 2.28, p = 0.034] (Figure 3I), and anterior commissure [t 20 = 2.18, p = 0.040] (Figure 3J) of 5xFAD;APOE4 mice, reflecting higher free water content in the 5xFAD;APOE4 mice than in the 5xFAD;APOE3 mice.”

Myelination was reduced in the corpus callosum of 5xFAD;APOE4 mice.

“Myelination was reduced in the corpus callosum of 5xFAD;APOE4 mice.”

Voxel-based morphometry revealed volume reduction in the striatum, external capsule, insular cortex, hippocampal commissure, corpus callosum, inferior colliculus, entorhinal cortex, and periaqueductal gray in 5xFAD;APOE4 mice compared to 5xFAD;APOE3 mice.

“Voxel‐based morphometry analysis revealed a volume reduction in the striatum, external capsule, insular cortex, hippocampal commissure, corpus callosum, inferior colliculus, entorhinal cortex, and periaqueductal gray, indicating atrophy of these brain regions in 5xFAD;APOE4 mice compared to 5xFAD;APOE3 mice (Figure S1A, B).”

The disrupted structural network nodes were the left entorhinal cortex, right insular cortex, right and left periaqueductal gray, and right and left cerebellum.

“In the disrupted network, the nodes were the left entorhinal cortex, right insular cortex, right and left periaqueductal gray, and right and left cerebellum.”

5xFAD;APOE4 mice had significantly lower neurite density index in the corpus callosum, hippocampal commissure, and anterior commissure than 5xFAD;APOE3 mice.

“We subsequently extracted tract‐specific NDI values and detected a significant reduction in the NDI in 5xFAD;APOE4 mice compared with 5xFAD;APOE3 mice across three major white matter tracts, corpus callosum [t 20 = 2.38, p = 0.028] (Figure 3C), hippocampal commissure [t 20 = 2.31, p = 0.034] (Figure 3D), and anterior commissure [t 20 = 2.44, p = 0.024] (Figure 3E).”

APOE4 reduced populations of mature and actively myelinating oligodendrocytes.

“Mechanistically, APOE4 reduced populations of mature and actively myelinating oligodendrocytes.”

• Also stated in: § Highlights · plain

  “APOE4 decreases the number of actively myelinating oligodendrocytes.”

Graph network metrics (assortativity, degree centrality, global efficiency, local efficiency, clustering coefficient, shortest path length, and small-worldness) did not significantly differ between 5xFAD;APOE4 and 5xFAD;APOE3 mice.

“Graph network metrics, such as assortativity (Figure 4D), degree centrality (Figure 4F), global efficiency (Figure 4G), local efficiency (Figure 4H), the clustering coefficient (Figure 4I), shortest path length (Figure 4J), and small‐worldness (Figure 4K), did not significantly differ between the two groups.”

APOE4 reduces betweenness centrality in the structural network.

“APOE4 disrupts structural connectivity and reduces the betweenness centrality.”

Orientation dispersion index did not differ between 5xFAD;APOE3 and 5xFAD;APOE4 mice in the corpus callosum, hippocampal commissure, and anterior commissure.

“Our mean ODI maps (Figure S2Ea,b) did not show any noticeable differences in the corpus callosum (Figure S2Ec), hippocampal commissure (Figure S2Ed), and anterior commissure (Figure S2Ee).”

Network-based statistical analysis revealed connectivity deficits in the entorhinal cortex, periaqueductal gray, and insular cortex of 5xFAD;APOE4 mice.

“Consistent with the findings of the voxel‐based morphometry analysis (Figure S1), the network‐based statistical analysis revealed connectivity deficits in the entorhinal cortex, periaqueductal gray, and insular cortex (Figure 4A, C).”

The number of BCAS1-positive actively myelinating oligodendrocytes was significantly lower in 5xFAD;APOE4 mice than in 5xFAD;APOE3 mice (t9 = 12.12, p = 0.0001).

“The number of anti‐BCAS1 antibody‐positive cells in 5xFAD;APOE4 mice was significantly lower [t 9 = 12.12, p = 0.0001] than that of 5xFAD;APOE3 mice (Figure 6I).”

MBP-positive area was significantly decreased in the corpus callosum of 5xFAD;APOE4 mice compared with 5xFAD;APOE3 mice (t9 = 2.86, p = 0.018).

“Consistent with the LFB results, we observed a significant decrease in the MBP‐positive area [t 9 = 2.86, p = 0.018] in the corpus callosum of 5xFAD;APOE4 mice (Figure 5G).”

MBP immunostaining exhibited a significant positive correlation with fractional anisotropy (p = 0.047).

“Notably, MBP immunostaining, a marker of myelination, exhibited a significant positive correlation with fractional anisotropy (p = 0.047) (Figure S4A).”

MBP immunostaining showed a significant negative correlation with radial diffusivity (p = 0.011).

“Conversely, MBP immunostaining showed a negative correlation with both radial diffusivity (p = 0.011) (Figure S4B) and isotropic volume fraction (p = 0.035) (Figure S4C).”

LFB intensity was significantly reduced in the corpus callosum of 5xFAD;APOE4 mice compared with 5xFAD;APOE3 mice (t9 = 3.85, p = 0.003).

“We detected a significant reduction in LFB intensity [t 9 = 3.85, p = 0.003] in the corpus callosum of 5xFAD;APOE4 mice compared with 5xFAD;APOE3 mice (Figure 5D).”

5xFAD;APOE4 mice had a marked disruption of structural connectivity compared with 5xFAD;APOE3 mice.

“Our results demonstrated that, compared with 5xFAD;APOE3, 5xFAD;APOE4 mice had significant reductions in fractional anisotropy (Figure 2H, I) and neurite density indices (Figure 3C, E) within major white matter tracts, along with a marked disruption of structural connectivity (Figure 4A, C).”

X-34-positive fibrillar plaques were markedly increased in the corpus callosum of 5xFAD;APOE4 mice.

“Our analysis revealed a marked increase in X‐34‐positive fibrillar plaques in the corpus callosum in 5xFAD;APOE4 mice (Figure S3C).”

MBP immunostaining showed a significant negative correlation with isotropic volume fraction (p = 0.035).

“Conversely, MBP immunostaining showed a negative correlation with both radial diffusivity (p = 0.011) (Figure S4B) and isotropic volume fraction (p = 0.035) (Figure S4C).”

There was no sex difference in amyloid levels in the corpus callosum of 5xFAD mice.

“Although sex differences in amyloid plaque deposition have been reported in the hippocampus and cortex of 5xFAD mice, we found no sex difference in amyloid levels in the corpus callosum (Figure S3D).”

5xFAD;APOE4 mice had higher isotropic volume fraction than 5xFAD;APOE3 mice.

“Notably, 5xFAD;APOE4 mice had higher isotropic volume fraction than 5xFAD; APOE3 mice (Figure 3H, J), suggesting increased accumulation of water in less myelinated white matter.”

5xFAD;APOE4 mice had significant reductions in neurite density indices within major white matter tracts compared with 5xFAD;APOE3 mice.

“Our results demonstrated that, compared with 5xFAD;APOE3, 5xFAD;APOE4 mice had significant reductions in fractional anisotropy (Figure 2H, I) and neurite density indices (Figure 3C, E) within major white matter tracts, along with a marked disruption of structural connectivity (Figure 4A, C).”

CC1-positive mature oligodendrocytes were significantly decreased in 5xFAD;APOE4 mice compared with 5xFAD;APOE3 mice (t9 = 2.50, p = 0.033).

“We observed a significant decrease in CC1‐positive mature oligodendrocytes in 5xFAD;APOE4 mice compared with those in 5xFAD;APOE3 mice [t 9 = 2.50, p = 0.033] (Figure 6F).”

• Also stated in: § Cellular mechanism of white matter integrity loss · plain

  “5xFAD;APOE4 mice had a reduced number of mature oligodendrocytes in the corpus callosum compared to 5xFAD;APOE3 mice (Figure 6F).”

Amyloid plaque deposition exhibited a significant negative correlation with NDI (p = 0.042).

“Amyloid plaque deposition exhibited a significant negative correlation with NDI (p = 0.042) (Figure S4D) and was positively correlated with isotropic volume fraction (p = 0.001) (Figure S4E).”

Microgliosis was significantly increased in 5xFAD;APOE4 mice.

“Concomitant with the observed increase in plaque deposition, we detected significantly increased microgliosis in 5xFAD;APOE4 mice (Figure S3G).”

There was no significant difference in the number of oligodendrocyte lineage cells between 5xFAD;APOE4 and 5xFAD;APOE3 mice (t9 = 1.01, p = 0.340).

“There was no significant difference in the number of oligodendrocyte lineage cells [t 9 = 1.01, p = 0.340] between the two genotypes (Figure 6C).”

IBA1 immunostaining was positively correlated with radial diffusivity (p = 0.001).

“Finally, We observed that IBA1 immunostaining, a marker of myeloid cell activation and neuroinflammation, was positively correlated with radial diffusivity (p = 0.001) (Figure S4F).”

Amyloid plaque deposition was positively correlated with isotropic volume fraction (p = 0.001).

“Amyloid plaque deposition exhibited a significant negative correlation with NDI (p = 0.042) (Figure S4D) and was positively correlated with isotropic volume fraction (p = 0.001) (Figure S4E).”

5xFAD;APOE4 mice had significant reductions in fractional anisotropy within major white matter tracts compared with 5xFAD;APOE3 mice.

“Our results demonstrated that, compared with 5xFAD;APOE3, 5xFAD;APOE4 mice had significant reductions in fractional anisotropy (Figure 2H, I) and neurite density indices (Figure 3C, E) within major white matter tracts, along with a marked disruption of structural connectivity (Figure 4A, C).”

The left entorhinal cortex of 5xFAD;APOE4 mice was at the center of the disrupted network connected with four edges.

“The left entorhinal cortex of 5xFAD;APOE4 mice was at the center of the disrupted network connected with four edges (Figure 4A, B).”

Conventional diffusion-weighted imaging cannot accurately quantify microstructural properties of brain tissues with non-Gaussian water diffusion, such as neurite density.

“Conventional diffusion‐weighted imaging (DWI) cannot accurately quantify microstructural properties of brain tissues with non‐Gaussian water diffusion, such as neurite density.”

Higher isotropic volume fraction in 5xFAD;APOE4 mice reflects higher free water content.

“reflecting higher free water content in the 5xFAD;APOE4 mice than in the 5xFAD;APOE3 mice.”

Increased radial diffusivity in 5xFAD;APOE4 mice suggests myelin loss.

“Because radial diffusivity reflects a magnitude of water diffusion perpendicular to axonal fibers, our data suggest that 5xFAD;APOE4 mice had myelin loss. 52”

• cites [52] Song SK, Yoshino J, Le TQ, et al. Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage. 2005; 26: 132‐ 140. 15862213 sourceNot checked — no full text of the source

APOE4 exacerbates white matter impairment in a mouse model of amyloid-beta amyloidosis by decreasing actively myelinating oligodendrocytes.

“Apolipoprotein ε4 exacerbates white matter impairment in a mouse model of Aβ amyloidosis by decreasing actively myelinating oligodendrocytes”

A decrease in the number of actively myelinating oligodendrocytes may explain myelin loss, leading to white matter impairments.

“Our results suggest that a decrease in the number of actively myelinating oligodendrocytes may explain myelin loss, leading to white matter impairments.”

The unchanged orientation dispersion index indicates that the remaining neurites retain their coherent alignment and directional organization typical of healthy white matter.

“Despite this reduction in neurite density, the ODI remained unchanged across these tracts, indicating that the remaining neurites retain their coherent alignment and directional organization typical of healthy white matter.”

APOE4 exacerbates white matter vulnerabilities in Alzheimer's disease.

“our data suggest that APOE4 exacerbates white matter vulnerabilities in AD.”

APOE4 impairs various parameters associated with white matter integrity in 5xFAD mice.

“Collectively, these findings demonstrate that APOE4 impairs various parameters associated with white matter integrity in 5XFAD mice.”

Decreased axial diffusivity in 5xFAD;APOE4 mice suggests axonal injury or degeneration.

“Because axial diffusivity reflects axonal integrity, the decreased values in 5xFAD;APOE4 mice suggest axonal injury or degeneration. 52”

• cites [52] Song SK, Yoshino J, Le TQ, et al. Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage. 2005; 26: 132‐ 140. 15862213 sourceNot checked — no full text of the source

No previous studies have validated in vivo white matter abnormalities detected by MRI with corresponding cellular changes in tissues.

“As a result, none have validated in vivo white matter abnormalities detected by MRI with corresponding cellular changes in tissues.”

Demyelination and neuroinflammation together may drive microstructural disorganization.

“Conversely, negative correlations of MBP with radial diffusivity (Figure S4B) and isotropic volume fraction (Figure S4C), as well as the positive correlation between IBA1 and radial diffusivity (Figure S4F), highlight that demyelination and neuroinflammation together may drive microstructural disorganization. 52”

• cites [52] Song SK, Yoshino J, Le TQ, et al. Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage. 2005; 26: 132‐ 140. 15862213 sourceNot checked — no full text of the source

• AssumptionRests on an assumption: Higher radial diffusivity and isotropic volume fraction are associated with increased water content and reduced myelin integrity.

The neuroinflammatory process contributes to increased water diffusion perpendicular to axonal fibers.

“This relationship implies that the neuroinflammatory process contributes to increased water diffusion perpendicular to axonal fibers.”

• AssumptionRests on an assumption: Higher radial diffusivity and isotropic volume fraction are associated with increased water content and reduced myelin integrity.

These reductions in mature and actively myelinating oligodendrocytes are likely underlying mechanisms for the observed impairment in white matter integrity and structural connectivity in 5xFAD;APOE4 mice.

“These reductions are likely to be underlying mechanisms for the observed impairment in white matter integrity (Figure 2) and structural connectivity (Figure 4A, C).”

Amyloid-driven neuroinflammation may disrupt myelin integrity, accelerating white matter impairment in 5xFAD mice.

“This amyloid‐driven neuroinflammation may disrupt myelin integrity, accelerating white matter impairment in 5xFAD mice.”

Myelination is decreased, particularly in the corpus callosum, in 5xFAD;APOE4 mice.

“These results collectively indicate decreased levels of myelination, particularly in the corpus callosum in 5xFAD;APOE4 mice.”

The reduction in BCAS1-positive cells indicates a marked decrease in active myelination in 5xFAD;APOE4 mice.

“This substantial reduction in the number of BCAS1‐positive cells suggests a marked decrease in active myelination in the 5xFAD;APOE4 mice.”

The disruption in connectivity in 5xFAD;APOE4 mice may be attributed to reduced fractional anisotropy and neurite density in the corpus callosum.

“This disruption in connectivity may be attributed to the reduced fractional anisotropy (Figure 2E) and neurite density (Figure 3C) in the corpus callosum of 5xFAD;APOE4 mice.”

Reduction in NDI in the APOE4 mouse model of Aβ amyloidosis indicates axonal loss.

“Consistent with these findings in humans, we also observed a reduction in NDI in the APOE4 mouse model of Aβ amyloidosis (Figure 3C, E), indicating axonal loss.”

• AssumptionRests on an assumption: Loss of axons and dendrites decreases the intraneurite space, reflected by a decrease in NDI.

The positive correlation between MBP and fractional anisotropy demonstrates that myelin integrity is associated with coherent white matter organization.

“The positive correlation between MBP and fractional anisotropy (Figure S4A) demonstrates that myelin integrity is associated with coherent white matter organization.”

The myelination deficits observed in this study might have emerged only in the presence of amyloid.

“These discrepancies suggest that the myelination deficits we observed might have emerged only in the presence of amyloid.”

Lower fractional anisotropy in 5xFAD;APOE4 mice demonstrates disrupted organization and demyelination in white matter tracts.

“5xFAD;APOE4 mice exhibit lower fractional anisotropy (Figure 2H, I), demonstrating disrupted organization and demyelination in white matter tracts. 51”

• cites [51] Beaulieu C. The basis of anisotropic water diffusion in the nervous system—a technical review. NMR Biomed. 2002; 15: 435‐ 455. 12489094 sourceNot checked — no full text of the source

Reduced myelination in 5xFAD;APOE4 mice is likely due to a decreased number of actively myelinating mature oligodendrocytes.

“We observed reduced myelination (Figure 5G) in 5xFAD;APOE4 mice, likely due to a decreased number of actively myelinating mature oligodendrocytes (Figure 6I).”

The disrupted structural connectivity suggests that nodes failed to physically connect in 5xFAD;APOE4 mice.

“The disrupted structural connectivity suggested that nodes failed to physically connect in 5xFAD;APOE4 mice.”

APOE4 compromises the integrity of white matter by reducing the population of actively myelinating oligodendrocytes.

“Therefore, our data suggest that APOE4 compromises the integrity of white matter by reducing the population of actively myelinating oligodendrocytes.”

Higher isotropic volume fraction in 5xFAD;APOE4 mice suggests increased accumulation of water in less myelinated white matter.

“Notably, 5xFAD;APOE4 mice had higher isotropic volume fraction than 5xFAD; APOE3 mice (Figure 3H, J), suggesting increased accumulation of water in less myelinated white matter.”

• AssumptionRests on an assumption: A reduction in NDI is often accompanied by expansion of the extraneurite space (higher ODI) or accumulation of cerebrospinal fluid (higher isotropic volume fraction).

The disrupted interhemispheric connections in 5xFAD;APOE4 mice are potentially connected through the corpus callosum.

“These disrupted interhemispheric connections are potentially connected through the corpus callosum.”

The study did not examine the independent effects of APOE3/4 apart from interactions with 5xFAD-driven amyloid pathology.

“Third, we did not examine the independent effects of APOE3/4 apart from its interactions with 5xFAD‐driven amyloid pathology.”

These results may help explain the higher prevalence of white matter hyperintensities in APOE4 carriers.

“These results provide new insight into the mechanisms underlying the increased susceptibility to white matter damage in APOE4 carriers and may help explain the higher prevalence of white matter hyperintensities observed in this population.”

Myelin loss may loosen axonal sheaths, enhancing perpendicular diffusion of water, leading to lower fractional anisotropy.

“Mechanistically, myelin loss may loosen axonal sheaths, enhancing perpendicular diffusion of water, leading to 52 lower fractional anisotropy.”

• cites [52] Song SK, Yoshino J, Le TQ, et al. Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage. 2005; 26: 132‐ 140. 15862213 sourceNot checked — no full text of the source

• AssumptionRests on an assumption: In healthy white matter, water diffuses primarily in the direction of myelinated axons.

APOE4 contributes to reduced numbers of mature and actively myelinating oligodendrocytes in the white matter of 5xFAD mice.

“Taken together, our findings demonstrate that APOE4 contributes to reduced numbers of mature (Figure 6F) and actively myelinating (Figure 6I) oligodendrocytes in the white matter of 5xFAD mice.”

The APOE4 isoform significantly reduces white matter integrity by decreasing the number of actively myelinating oligodendrocytes.

“Importantly, we demonstrated that the APOE4 isoform significantly reduces white matter integrity by decreasing the number of actively myelinating oligodendrocytes.”

This study is the first to apply NODDI-MRI to examine microstructural tissue integrity in an amyloid mouse model with human APOE isoforms.

“Despite these limitations, this study is the first to apply the advanced NODDI‐MRI approach to examine microstructural tissue integrity in an amyloid mouse model with human APOE isoforms.”

A reduction in mature oligodendrocytes may contribute to myelin deficits and white matter abnormalities in the presence of APOE4 allele.

“Taken together, this result suggests that a reduction in mature oligodendrocytes may contribute to myelin deficits and white matter abnormalities in the presence of APOE4 allele.”

The reduction in the number of both mature and actively myelinating oligodendrocytes contributes to impaired myelination and loss of white matter integrity in 5xFAD;APOE4 mice.

“Overall, our findings suggest that the reduction in the number of both mature and actively myelinating oligodendrocytes contributes to impaired myelination and the loss of white matter integrity in 5xFAD;APOE4 mice.”

Actively myelinating oligodendrocytes are key contributors to white matter impairment in AD.

“Our findings provide new evidence that these actively myelinating oligodendrocytes are key contributors to white matter impairment in AD.”